US8071363B2 - Chip for cell electrophysiological sensor, cell electrophysiological sensor using the same, and manufacturing method of chip for cell electrophysiological sensor - Google Patents

Chip for cell electrophysiological sensor, cell electrophysiological sensor using the same, and manufacturing method of chip for cell electrophysiological sensor Download PDF

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Publication number
US8071363B2
US8071363B2 US11/914,283 US91428307A US8071363B2 US 8071363 B2 US8071363 B2 US 8071363B2 US 91428307 A US91428307 A US 91428307A US 8071363 B2 US8071363 B2 US 8071363B2
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hole
substrate
chip
electrophysiological sensor
cell electrophysiological
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US20090152110A1 (en
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Soichiro Hiraoka
Masaya Nakatani
Hiroshi Ushio
Akiyoshi Oshima
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Panasonic Corp
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Panasonic Corp
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Assigned to PANASONIC CORPORATION reassignment PANASONIC CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: MATSUSHITA ELECTRIC INDUSTRIAL CO., LTD.
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
    • G01N33/48728—Investigating individual cells, e.g. by patch clamp, voltage clamp

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  • the present invention relates to a chip used in cell electrophysiological sensor for measuring electrophysiological activities of cells, a cell electrophysiological sensor using this chip, and a manufacturing method of chip for cell electrophysiological sensor.
  • the existing cell electrophysiological sensor 1 (substrate probe) includes a substrate 2 and an electrode jar 3 disposed above the substrate 2 .
  • the substrate 2 has a through-hole 5 penetrating through the substrate 2 from its upside to downside.
  • a first electrode 6 is disposed, and a second electrode 7 is disposed inside of the through-hole 5 .
  • the second electrode 7 is coupled to a signal detector (not shown) by way of a wiring 8 .
  • the operating method of the cell electrophysiological sensor 1 is explained below.
  • an electrolyte solution 9 and a sample cell 10 are poured into the electrode jar 3 .
  • the sample cell 10 is trapped and held at an opening 4 of the through-hole 5 .
  • the sample cell 10 is sucked by a suction pump or the like from beneath the through-hole 5 , and is held in contact with the opening 4 .
  • This through-hole 5 plays the same role as the leading end hole in the micropipette.
  • the function and pharmacological reaction of the ion channel of the sample cell 10 are analyzed by measuring the voltage or current before and after reaction between the first electrode 6 and second electrode 7 , and determining the potential difference inside and outside of the cell (see, for example, patent document 1).
  • the invention is intended to encourage the flow of electrolyte solution flowing in and out of the through-hole, and to enhance the trapping rate of sample cells.
  • the invention has the through-hole penetrating through the substrate from its upside to downside, in which the inner wall of the through-hole and the substrate surface are linked on a curved surface.
  • the electrolyte solution flows easily in and out of the through-hole, and the trapping rate of sample cells can be enhanced.
  • the opening of the through-hole is formed in a curved surface smoothly linking with the substrate surface, and changes of sectional area of passage from the electrode jar to the inside of the through-hole are moderate, and the resistance loss of fluid is decreased.
  • the electrolyte solution is allowed to flow easily in and out of the through-hole, and the sample cell is trapped accurately, and the trapping rate is enhanced.
  • FIG. 1 is a sectional view of cell electrophysiological sensor in a preferred embodiment of the invention.
  • FIG. 2 is a sectional view of substrate (part Y in FIG. 1 ) in a preferred embodiment of the invention.
  • FIG. 3 is an essential magnified sectional view of operation of cell electrophysiological sensor in a preferred embodiment of the invention.
  • FIG. 4 is a perspective view of substrate in a preferred embodiment of the invention.
  • FIG. 5 is a sectional view of manufacturing process of substrate in a preferred embodiment of the invention.
  • FIG. 6A is an essential sectional view of substrate in a preferred embodiment of the invention.
  • FIG. 6B is an essential sectional view of the same.
  • FIG. 6C is an essential sectional view of the same.
  • FIG. 6D is an essential sectional view of the same.
  • FIG. 7 is a sectional view of manufacturing process of substrate in a preferred embodiment of the invention.
  • FIG. 8 is a sectional view of manufacturing process of the substrate.
  • FIG. 9 is a sectional view of manufacturing process of the substrate.
  • FIG. 10 is a perspective view of substrate in a preferred embodiment of the invention.
  • FIG. 11 is a sectional view of substrate in a preferred embodiment of the invention.
  • FIG. 12 is a sectional view of chip in a preferred embodiment of the invention.
  • FIG. 13 is a sectional view of manufacturing process of chip in a preferred embodiment of the invention.
  • FIG. 14 is a sectional view of manufacturing process of the chip.
  • FIG. 15 is a sectional view of manufacturing process of the chip.
  • FIG. 16 is a sectional view of substrate in a preferred embodiment of the invention.
  • FIG. 17 is its sectional view.
  • FIG. 18 is its sectional view.
  • FIG. 19 is a sectional view of manufacturing process of substrate in a preferred embodiment of the invention.
  • FIG. 20 is a sectional view of manufacturing process of the substrate.
  • FIG. 21 is a sectional view of manufacturing process of the substrate.
  • FIG. 22 is a sectional view of substrate in a preferred embodiment of the invention.
  • FIG. 23 is its sectional view.
  • FIG. 24 is its sectional view.
  • FIG. 25 is its sectional view.
  • FIG. 26 is a sectional view of cell electrophysiological sensor in a prior art.
  • FIG. 1 is a sectional view of cell electrophysiological sensor in preferred embodiment 1
  • FIG. 2 is a sectional view of a substrate used therein
  • FIG. 3 is an essential magnified sectional view of operation of the cell electrophysiological sensor
  • FIG. 4 is a perspective view of the substrate.
  • the upper direction refers to the direction of arrow X in FIG. 1 .
  • the cell electrophysiological sensor 11 in preferred embodiment 1 includes a chip 36 having a substrate 12 , a first electrode jar 13 disposed above the substrate 12 , a first electrode 14 disposed inside of the first electrode jar 13 and on the upside of the substrate 12 , a second electrode jar 15 disposed beneath the substrate 12 , and a second electrode 16 disposed inside of the second electrode jar 15 and on the downside of the substrate 12 , and a through-hole 17 penetrates through the substrate 12 from its upside to downside.
  • FIG. 2 The part Y surrounded by dotted line in FIG. 1 is magnified in FIG. 2 , in which openings 17 A, 17 B are curved from the upside and downside of the substrate 12 toward the inner side of the through-hole 17 , and are formed in a smooth curved surface linking to the inside of the through-hole 17 .
  • the inner wall of the through-hole 17 is curved to the inner side of the through-hole 17 , and is formed in a smooth curved surface projecting nearly at the central point in the depth direction of the through-hole 17 .
  • the aperture of the through-hole 17 is the minimum inside diameter at the central point or near the central point in the depth direction of the through-hole 17 , and is gradually increased toward the openings 17 A, 17 B.
  • the outer circumference of the openings 17 A, 17 B has bulges 18 A, 18 B smoothly building up on the surface of the substrate 12 .
  • the bulge 18 A is formed on the substrate 12 so that the distance r 1 from the outermost circumference of the bulge 18 A to the center of the opening 17 A may be shorter than the radius of the sample cell 19 .
  • the square average roughness of Rq is defined by the square root of average values of square of deviation from the average to the measured value.
  • the radius of sample cell 19 was measured by impregnating the sample cell 19 in physiological saline, and waiting until the osmotic pressure inside and outside the cell was balanced.
  • the substrate 12 of the chip 36 is a silicon substrate 12 , and as shown in FIG. 4 , a plurality of through-holes 17 are formed in the substrate 12 .
  • the minimum inside diameter of the through-hole 17 is 3 ⁇ m.
  • the inside diameter of the through-hole 17 can be determined depending on the size, shape or properties of the cell to be measured. For example, when the size of the sample cell 19 is about 5 to 50 ⁇ m, in order to enhance the contact tightness between the sample cell 19 and opening 17 A, the minimum inside diameter of the through-hole 17 is preferred to be 3 ⁇ m or less. The depth of the through-hole 17 is 15 ⁇ m or less.
  • the first electrode jar 13 is filled with first electrolyte solution 20 (cell outer fluid) containing the sample cell 19
  • the second electrode jar 15 is filled with second electrolyte solution 21 (cell inner fluid).
  • first electrolyte solution 20 cell outer fluid
  • second electrolyte solution 21 cell inner fluid
  • the sample cell 19 is a mammal muscular cell
  • the first electrolyte solution 20 is an electrolyte solution containing K + ions by about 4 mM, Na + ions by about 145 mM, and Cl ⁇ ions by about 123 mM
  • the second electrolyte solution 21 is an electrolyte solution containing K + ions by about 155 mM, Na + ions by about 12 mM, and Cl ⁇ ions by about 4.2 mM.
  • the same composition may be used for the first electrolyte solution 20 and second electrolyte solution 21 .
  • a fine pore By sucking from the downside of the substrate 12 , or by administering a medicine (e.g. Nystatin) from beneath the substrate 12 , a fine pore can be formed in the sample cell 19 .
  • a medicine e.g. Nystatin
  • a stimulating action on the sample cell 19 is applied from above the substrate 12 .
  • Stimulation includes many varieties, such as chemical drug, poison, other chemical simulation, mechanical dislocation, light, heat, electricity, electromagnetic wave, and other physical simulation.
  • the sample cell 19 reacts actively to such stimulation, for example, the sample cell 19 releases or absorbs various ions through a channel of cell membrane. As a result, the potential gradient inside and outside the cell is changed, and the change is detected by the first electrode 14 and second electrode 16 shown in FIG. 1 , and, for example, the pharmacological reaction of the cell can be studied.
  • FIG. 5 to FIG. 9 are sectional views for explaining the manufacturing method of the substrate 12 of the cell electrophysiological sensor 11
  • FIG. 10 is a perspective view thereof.
  • a resist mask 22 is formed on the upside of the silicon substrate 12 .
  • a mask hole 23 of almost same shape as the section of the desired through-hole 17 is patterned.
  • the etching method is preferred to be dry etching capable of processing finely at high precision.
  • etching promoting gas etching gas
  • etching suppressing gas etching suppressing gas
  • SF 6 is used as etching gas
  • C 4 F 8 is used as suppressing gas.
  • plasma is generated by induction coupling method of external coil, and SF 6 is introduced as etching gas, and F radicals are generated, and the F radicals react with the substrate 12 and the substrate 12 is etched chemically.
  • C 4 F 8 sticks to the wall of the dry etching hole of the substrate 12 without being deflected, and a uniform film is formed.
  • This film of CF + becomes a protective film, and suppresses etching.
  • the protective film is formed not only in the wall but also in the bottom of the through-hole 17 , but the protective film formed in the bottom is easily removed by the ion impact relatively as compared with the protective film formed in the wall, and etching progresses downward.
  • etching progresses not only in downward direction but also in lateral direction isotropically, and undulations are formed in the wall of the through-hole 17 as shown in FIG. 6C .
  • a through-hole 17 having perpendicular undulations in the flow direction of electrolyte solution is formed.
  • the boundary of the inner wall of the through-hole 17 and the surface of the substrate 12 is formed in a sharp corner.
  • FIG. 7 is a sectional view of substrate 12 omitting the undulations of the through-hole 17 .
  • CF 4 may be used as etching gas, and CHF 3 as suppressing gas.
  • the resist mask 22 is removed, and the substrate 12 is heated (annealed) to 1000° C. or more in the atmosphere of decompressed rare gas, hydrogen gas or nitrogen gas.
  • the gas usable at this time is any one of helium, neon, argon, krypton, xenon, hydrogen, and nitrogen, or a mixture thereof.
  • the diffusion speed varies significantly depending on the pressure, and the diffusion can be controlled at high precision, and it is effective in the aspect of the production.
  • the pressure of inert gas atmosphere is preferably controlled under 27 kPa. As a result, a desired shape can be realized at high speed.
  • silicon When silicon is used as the substrate 12 , it is needed to anneal at 1000° C. or higher in order to obtain enough energy for inducing surface self-diffusion phenomenon of silicon.
  • Such surface self-diffusion phenomenon is obtained in other material than silicon such as SiO 2 by varying the annealing condition (the type of inert gas or annealing temperature), and such materials may be also used as the material of the substrate 12 .
  • the annealing condition the type of inert gas or annealing temperature
  • Non-annealing method includes, for example, chemical vapor deposition method (CVD method) of forming films of silicon or other material sequentially from the upside to downside of the substrate 12 , and a similar shape is obtained.
  • CVD method chemical vapor deposition method
  • various materials other than silicon can be selected, and a configuration in consideration of affinity of cell and substrate 12 may be realized.
  • the cell electrophysiological sensor 11 in preferred embodiment 1 is capable of enhancing the smoothness of flow of electrolyte solution (first electrolyte solution 20 and second electrolyte solution 21 ) flowing in and out of the through-hole 17 , thereby enhancing the trapping rate of sample cells 19 . The reason is explained below.
  • the openings 17 A, 17 B of the through-hole 17 and the inner wall of the through-hole 17 are formed in a smooth curved surface curved at the inner side of the through-hole 17 , as mentioned above, from the surface of the substrate 12 toward the inside of the through-hole 17 .
  • the sectional area change of the passage is made moderate and the resistance loss of the fluid is reduced.
  • the electrolyte solution (first electrolyte solution 20 and second electrolyte solution 21 ) flowing in and out of the through-hole is smooth in flow, and the sample cell 19 is sucked accurately, and the trapping rate into the opening 17 A is enhanced.
  • the inner wall of the through-hole 17 is in a curved surface being curved to the inner side of the through-hole 17 , and projecting outward near the central point of the through-hole 17 , and the inside diameter of the through-hole 17 is increased gradually from the central point of the through-hole 17 toward the openings 17 A, 17 B of the through-hole 17 .
  • the flow velocity reaches the maximum at the central point of the through-hole 17 , and bubbles are forced out by its water pressure. Since it is hard to remove bubbles in the inner parts of the through-hole 17 , this structure is very useful for decreasing the bubbles.
  • the bulge 18 B is formed around the opening 17 B of the through-hole 17 at the downside of the substrate 12 , measuring errors can be decreased. This is considered because, generally, the bubbles forced out from the through-hole 17 stick to the downside of the substrate 12 , which cause measuring errors by increase of resistance component, but by forming the bulge 18 B, the bubbles can be released to the second electrode jar 15 along the slope of the bulge 18 B.
  • the sample cell is trapped along the curved surface of the opening 17 A, the contact tightness of the sample cell 19 and the opening 17 A of the through-hole 17 is increased, and it is easy to maintain the tight state, so that the measuring precision of the cell electrophysiological sensor 11 may be enhanced.
  • the contact tightness of the sample cell 19 and the opening 17 A of the through-hole 17 is increased, and a high sealing performance is obtained.
  • the bulge 18 A the contact area of the sample cell 19 and the opening 17 A is increased.
  • the distance r 1 from the outermost circumference of the bulge 18 A to the center of the opening 17 A of the through-hole 17 shorter than the radius of the sample cell 19 the contact area of the opening 17 A and the sample cell 19 can be further increased.
  • the sample cell 19 is accurately held tightly to the opening 17 A, and the measuring precision of the cell electrophysiological sensor 11 can be enhanced.
  • the bulge 18 A is formed at the upside of the substrate 12 and the bulge 18 B at the downside, but as shown in the sectional view in FIG. 9 and the perspective view in FIG. 10 , if neither bulge 18 A nor 18 B is formed, by forming the openings 17 A, 17 B on a curved surface linking with the surface of the substrate 12 , the electrolyte solution flows smoothly, bubbles are decreased, and the contact tightness of the cell and the opening 17 A of the through-hole 17 can be enhanced.
  • FIG. 11 is a sectional view of a substrate of cell electrophysiological sensor in preferred embodiment 2.
  • the configuration of the substrate 12 used in the cell electrophysiological sensor in preferred embodiment 2 is as shown in FIG. 11 , in which the both sides of the substrate 12 and the inner wall surface of the through-hole 17 are covered with an insulating layer 24 .
  • the sample cell 19 can be held tightly in the opening 17 A.
  • the hydrophilic property is enhanced in the portion contacting with the electrolyte solution (first electrolyte solution 20 and second electrolyte solution 21 ), and bubbles can be effectively suppressed.
  • the insulating layer 24 formed of silicon oxide or silicon nitride can be manufactured easily by oxidizing process or nitriding process, and the productivity is enhanced at the same time.
  • Preferred embodiment 3 differs from preferred embodiment 1 in that a silicon oxide layer is laminated as oxide layer 25 preliminarily at one side of the substrate 12 as shown in a sectional view of a chip 36 shown in FIG. 12 .
  • a resist mask 28 having a hole is formed, and as shown in FIG. 14 , a through-hole 17 is formed by etching from the side of the silicon layer 26 of the substrate 12 .
  • the upper silicon layer 26 of two silicon layers 26 becomes the substrate 12 as shown in FIG. 12 .
  • the oxide layer 25 (silicon oxide) is lower in etching rate than the silicon layer 26 , by etching from the silicon layer 26 , etching stops at the oxide layer 25 , and the depth of the through-hole 17 and thickness of the substrate 12 (substrate 12 in FIG. 12 ) can be managed at high precision.
  • a hole 30 (hole 30 in FIG. 12 ) is formed at a position corresponding to the through-hole 17 of the oxide layer 25 .
  • a proper gas for etching the oxide layer 25 is, for example, CF 4 .
  • a resist mask 29 is formed on the silicon layer 26 , and the silicon layer 26 is etched.
  • the substrate 12 is heated, or films are formed by vapor phase method from both sides of the substrate 12 , and the chip 36 shown in FIG. 12 is formed.
  • the oxide layer 25 may be also positioned at the upside of the substrate 12 , that is, at the side of trapping the sample cell, or may be disposed at the downside of the substrate 12 .
  • the oxide layer 25 may be also positioned at the upside of the substrate 12 , or when desired to improve flow above the substrate, the oxide layer 25 may be also positioned at the downside of the substrate 12 .
  • a bulge 18 may be formed as shown in FIG. 17 .
  • the substrate 12 used in the cell electrophysiological sensor 11 in preferred embodiment 4 includes a recess 32 formed in the upside (first side) of the substrate 12 , and a through-hole 17 penetrating from the recess 32 to the downside (second side) of the substrate 12 .
  • Openings 17 A, 17 B of the through-hole 17 are formed in a smooth curved surface, and the upside of the substrate 12 and the inner wall of the recess 32 , the inner wall of the recess 32 and the inner wall of the through-hole 17 , and the inner wall of the through-hole 17 and the downside of the substrate 12 are respectively linked in a curved surface.
  • the recess 32 spreads outward from the opening 17 A of the through-hole 17 , and is formed in a curved surface linking to the upside of the substrate 12 , and the through-hole 17 is formed from the deepest position of the recess 32 .
  • the shape of the recess 32 is hemispherical or nearly hemispherical.
  • the hemispherical or nearly hemispherical shape when the sample cell is a true sphere, the cell can be held easily without being distorted.
  • the diameter of the opening 32 A of the recess 32 is desired to be about 30 ⁇ m.
  • a resist mask 33 is formed on the upside of the silicon substrate 12 .
  • a mask hole 34 of nearly same shape as the section of desired through-hole 17 is patterned.
  • etching the substrate 12 by etching the substrate 12 , a recess 32 is formed.
  • the etching method at this time is desired to be dry etching of high precision and fine processing.
  • a desired etching gas is SF 6 , CF 4 , NF 3 , XeF 2 , or mixed gas thereof. These gases are effective to promote silicon etching not only in the depth direction but also in the horizontal direction, and the substrate 12 can be etched precisely in a bowl shape.
  • the etching promoting gas is mixed with carrier gas such as N 2 , Ar, He, or H 2 .
  • a through-hole 17 is formed to penetrate in the perpendicular direction from the bottom of the recess 32 to the downside of the substrate 12 .
  • dry etching is processed by using etching gas and suppressing gas alternately.
  • the resist mask 33 is removed, and the substrate 12 is heated at 1000° C. or higher in decompressed inert gas atmosphere same as in preferred embodiment 1, and the substrate 12 ( FIG. 18 ) having a smooth curvature of preferred embodiment 4 is manufactured.
  • films of same shape can be formed by vapor phase method same as in preferred embodiment 1.
  • the upside of the substrate 12 and the inner wall of the recess 32 , the inner wall of the recess 32 and the inner wall of the through-hole 17 , and the inner wall of the through-hole 17 and the downside of the substrate 12 are respectively linked in a curved surface.
  • sudden sectional area changes of passage are suppressed, the resistance loss of fluid is decreased, the flow of electrolyte solutions 20 , 21 (see FIG. 3 ) flowing in and out of the through-hole 17 is made smoother, and the trapping rate of sample cells is enhanced, and the measuring precision of the cell electrophysiological sensor 11 is improved.
  • the recess 32 at the upside of the substrate 12 , it is easier to trap the sample cell 19 , and it is easier to maintain the trapped sample cell 19 .
  • the contact area of the opening 17 A of the through-hole 17 and the sample cell 19 is increased, and the contact tightness of the opening 17 A of the through-hole 17 and the sample cell 19 is improved.
  • the through-hole 17 is formed at the deepest position of the recess 32 , it is easier to align the sample cell 19 trapped in the recess 32 into the opening 17 A of the through-hole 17 . As a result, the trapping rate of sample cells is increased.
  • the recess 32 is hemispherical, but the recess 32 may formed in other shape, as shown in FIG. 22 , such as conical or nearly conical shape.
  • the recess 32 is formed in conical or nearly conical shape, if the slope of the recess 32 is steep and the sample cell is a sticky cell, the cell can be trapped efficiently in the through-hole 17 without being stuck somewhere in the recess 32 .
  • an insulating layer (not shown) is formed between the surface of the substrate 12 shown in FIG. 18 , and the recess 32 and inner wall of the through-hole 17 , an electric insulation is enhanced between the upside and downside of the substrate 12 .
  • an oxide layer (not shown) may be laminated preliminarily on the downside (second side) of the substrate 12 .
  • an insulating layer (not shown) may be formed between the upside of the substrate 12 , the recess 32 and inner wall of the through-hole 17 .
  • a bulge (not shown) building up outward may be formed on the outer circumference of the openings 17 A, 17 B of the through-hole 17 .
  • the contact area of the sample cell 19 and the opening 17 A is increased, and bubbles staying in the opening 17 B of the through-hole 17 may be decreased.
  • multiple recesses 32 may be formed on the upside of the substrate 12 , and the inner walls of the adjacent recesses 32 may be crossed each other.
  • the upside of the substrate 12 there is almost no flat part in the region of forming the recesses 32 , and if the sample cell contacts with the intersection 35 , it is not stuck, and is inclined to either recess 32 by gravity, and is aligned to the center of the recess 32 along the inner wall.
  • intersection 35 may be formed in a smooth curved surface by annealing or other process, and the contacting sample cell can be safely guided into the opening 17 A of the through-hole 17 without being injured.
  • preferred embodiment 5 is similar to preferred embodiment 4 except that the substrate is turned upside down.
  • the substrate 12 used in the cell electrophysiological sensor 11 of preferred embodiment 5 includes a recess 32 formed at the downside of the substrate 12 , and a through-hole 17 penetrating from the recess 32 to the upside of the substrate 12 .
  • Openings 17 C, 17 D of the through-hole 17 are formed in a smooth curved surface, and the downside of the substrate 12 and the inner wall of the recess 32 , the inner wall of the recess 32 and the inner wall of the through-hole 17 , and the inner wall of the through-hole 17 and the upside of the substrate 12 are respectively linked in a curved surface.
  • the recess 32 spreads outward from the opening 17 D of the through-hole 17 , and is formed in a curved surface linking to the downside of the substrate 12 , and the through-hole 17 is formed from the deepest position of the recess 32 .
  • the resistance loss of the fluid is smaller. Further, since the downside of the substrate 12 and the inner wall of the recess 32 , the inner wall of the recess 32 and the inner wall of the through-hole 17 , and the inner wall of the through-hole 17 and the upside of the substrate 12 are respectively linked in a curved surface, the fluid resistance can be further reduced.
  • the recess 32 is formed beneath the substrate 12 , it is easier to suck the second electrolyte solution 21 (second electrode 21 in FIG. 1 ) from beneath the substrate 12 , and the contact tightness of the sample cell 19 and the opening 17 C of the through-hole 17 is enhanced. Besides, since the recess 32 is formed beneath the substrate 12 , it is easier to distribute the medicine (such as Nystatin) injected from beneath the substrate 12 into the through-hole 17 .
  • the medicine such as Nystatin
  • an electric insulation is enhanced between the first electrode jar 13 and second electrode jar 15 shown in FIG. 1 .
  • the oxide layer 25 may be laminated on the upside of the substrate 12 .
  • the thickness of the substrate 12 can be managed at high precision.
  • an insulating layer (not shown) may be formed on the downside of the substrate 12 and the recess 32 and the inner wall of the through-hole 17 .
  • the bulge 18 building up outward may be formed on the outer circumference of the openings 17 C, 17 D of the through-hole 17 .
  • the bulge 18 is formed above the through-hole 17 , it is easier to trap the sample cell 19 in the opening 17 C, and the contact area of the sample cell 19 and the opening 17 C increases. Or when the bulge 18 is formed beneath the through-hole 17 , bubbles staying in the opening 17 D can be decreased.
  • the cell electrophysiological sensor of the invention is capable of sucking the cells accurately, and trapping and holding precisely in the opening of the through-hole, and is hence very useful in the field of medical and biological applications where measurement of high precision and high efficiency is demanded.

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US11/914,283 2006-05-25 2007-05-21 Chip for cell electrophysiological sensor, cell electrophysiological sensor using the same, and manufacturing method of chip for cell electrophysiological sensor Expired - Fee Related US8071363B2 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
JP2006-144801 2006-05-25
JPJP2006-144801 2006-05-25
JP2006144801 2006-05-25
JP2007-020834 2007-01-31
JP2007020834 2007-01-31
JPJP2007-020834 2007-01-31
PCT/JP2007/060326 WO2007138902A1 (ja) 2006-05-25 2007-05-21 細胞電気生理センサ用チップとこれを用いた細胞電気生理センサおよび細胞電気生理センサ用チップの製造方法

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PCT/JP2007/059743 Continuation-In-Part WO2007132769A1 (ja) 2002-06-05 2007-05-11 細胞電位測定デバイスとそれに用いる基板、細胞電位測定デバイス用基板の製造方法
US11/913,116 Continuation-In-Part US20100019756A1 (en) 2006-05-17 2007-05-11 Device for measuring cellular potential, substrate used for the same and method of manufacturing substrate for device for measuring cellular potential
PCT/JP2007/060326 A-371-Of-International WO2007138902A1 (ja) 2002-06-05 2007-05-21 細胞電気生理センサ用チップとこれを用いた細胞電気生理センサおよび細胞電気生理センサ用チップの製造方法

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US11/916,947 Continuation-In-Part US20100019782A1 (en) 2005-06-29 2006-06-28 Cellular potential measurement container
PCT/JP2006/313359 Continuation-In-Part WO2007001091A1 (en) 2002-06-05 2006-06-28 Cellular potential measurement container

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US8071363B2 true US8071363B2 (en) 2011-12-06

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